title: Morelloflavone blocks injury-induced neointimal formation by inhibiting vascular smooth muscle cell migration.
abstract: BACKGROUND
  In-stent restenosis, or renarrowing within a coronary stent, is the most ominous complication of percutaneous coronary intervention, caused by vascular smooth muscle cell (VSMC) migration into and proliferation in the intima. Although drug-eluting stents reduce restenosis, they delay the tissue healing of the injured arteries. No promising alternative anti-restenosis treatments are currently on the horizon.
  
  
  METHODS
  In endothelium-denudated mouse carotid arteries, oral morelloflavone-an active ingredient of the Thai medicinal plant Garcinia dulcis-significantly decreased the degree of neointimal hyperplasia, without affecting neointimal cell cycle progression or apoptosis as evaluated by Ki-67 and TUNEL staining, respectively. At the cellular level, morelloflavone robustly inhibited VSMC migration as shown by both scratch wound and invasion assays. In addition, morelloflavone prevented VSMCs from forming lamellipodia, a VSMC migration apparatus. Mechanistically, the inhibition by morelloflavone of VSMC migration was through its negative regulatory effects on several migration-related kinases, including FAK, Src, ERK, and RhoA. Consistently with the animal data, morelloflavone did not affect VSMC cell cycle progression or induce apoptosis.
  
  
  RESULTS
  These data suggest that morelloflavone blocks injury-induced neointimal hyperplasia via the inhibition of VSMC migration, without inducing apoptosis or cell cycle arrest.
  
  
  CONCLUSIONS
  We propose morelloflavone to be a viable oral agent for the prevention of restenosis, without compromising effects on the integrity and healing of the injured arteries.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Decha
authors.initials: D
authors.lastname: Pinkaew
authors.forename: Sung Gook
authors.initials: SG
authors.lastname: Cho
authors.forename: David Y
authors.initials: DY
authors.lastname: Hui
authors.forename: John E
authors.initials: JE
authors.lastname: Wiktorowicz
authors.forename: Nongporn
authors.initials: N
authors.lastname: Hutadilok-Towatana
authors.forename: Wilawan
authors.initials: W
authors.lastname: Mahabusarakam
authors.forename: Moltira
authors.initials: M
authors.lastname: Tonganunt
authors.forename: Lewis J
authors.initials: LJ
authors.lastname: Stafford
authors.forename: Amornrat
authors.initials: A
authors.lastname: Phongdara
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.forename: Ken
authors.initials: K
authors.lastname: Fujise
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D017209:Apoptosis; D044946:Biflavonoids / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology; D016893:Carotid Stenosis / Q000473:pathology / Q000517:prevention & control; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D029760:Garcinia / Q000737:chemistry*; D006965:Hyperplasia; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000502:physiology; D011554:Pseudopodia / Q000187:drug effects; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; D044946:Biflavonoids; C105620:morelloflavone